Non-proteolytic ubiquitination of HBx controls HBV replication

Xiangpeng Sheng; Yi Yang; Min Zhu; Linlin Zhou; Fang Zhu; Yuanfei Zhu; Siying Dong; Hui Kong; Honghua Wang; Ji Jiang; Mingyue Wan; Mingyang Feng; Qiang Deng; Yumin Xu; Qing You; Ronggui Hu

doi:10.1016/j.virs.2024.01.008

April 2024

. doi: 10.1016/j.virs.2024.01.008

Citation: Xiangpeng Sheng, Yi Yang, Min Zhu, Linlin Zhou, Fang Zhu, Yuanfei Zhu, Siying Dong, Hui Kong, Honghua Wang, Ji Jiang, Mingyue Wan, Mingyang Feng, Qiang Deng, Yumin Xu, Qing You, Ronggui Hu. Non-proteolytic ubiquitination of HBx controls HBV replication .VIROLOGICA SINICA, 2024, 39(2) : 338-342. http://dx.doi.org/10.1016/j.virs.2024.01.008

乙肝病毒X蛋白的非降解性泛素化修饰限制了乙肝病毒的复制

盛相鹏 ^a,b,c,, ,
杨奕 ^d ,
朱旻 ^e ,
周琳琳 ^f ,
朱芳 ^g ,
朱园飞 ^h ,
董思莹 ^b ,
孔惠 ^a ,
汪红花 ^c ,
江吉 ^e ,
万明月 ⁱ ,
冯明洋 ⁱ ,
邓强 ^h ,
徐玉敏 ^i,, ,
尤青 ^j,, ,
胡荣贵 ^b,c,,

a. 中国农业科学院哈尔滨兽医研究所;
b. 中国科学院分子细胞科学卓越创新中心;
c. 国科大杭州高等研究院生命科学学院d. 上海交通大学医学院附属瑞金医院胸外科;
e. 上海师范大学生命科学学院;
f. 四川大学华西基础医学与法医学院;
g. 贵州大学医学院;
h. 复旦大学基础医学院;
i. 上海交通大学医学院附属瑞金医院感染科;
j. 上海交大生物医学工程学院

通讯作者： 盛相鹏, shengxiangpeng@ucas.ac.cn; 徐玉敏, xym121@163.com; 尤青, youqing@sjtu.edu.cn; 胡荣贵, coryhu@sibcb.ac.cn
收稿日期： 2023-04-14
录用日期： 2024-01-24

摘要

乙型肝炎病毒（HBV）感染是肝细胞癌形成的主要原因，目前仍然严重危害人类健康。乙型肝炎病毒表达一种多功能的X蛋白（HBx），该蛋白不仅仅影响宿主细胞的许多生命活动，还能通过招募DDB1相关的E3泛素连接酶来降解宿主Smc5/6，从而促进HBV感染。尽管大量的研究拓宽了我们对HBx功能的了解，但针对HBx的调控机制还没有充分阐释。在这项研究中，我们发现宿主的E3泛素连接酶TRIM21可以通过对HBx进行非降解性的泛素修饰来抑制HBV的感染和复制。我们发现TRIM21在细胞内的表达水平与HBV的复制呈现负相关的关系。并且，TRIM21可以直接结合HBx蛋白并催化了HBx上非赖氨酸位点的泛素修饰，此种泛素化修饰并不影响HBx的稳定性。更为重要的是，突变了泛素化位点的HBx可以更强地招募DDB1，并促进HBV的复制。这些研究结果为我们更好地理解HBx的调节机制提供了基础，并为针对HBV感染的药物开发提供新思路。
- 乙型肝炎病毒
- , HBx蛋白
- , 泛素化修饰
- , 非降解
- , TRIM21

Non-proteolytic ubiquitination of HBx controls HBV replication

Xiangpeng Sheng ^a,b,c,, ,
Yi Yang ^d ,
Min Zhu ^e ,
Linlin Zhou ^f ,
Fang Zhu ^g ,
Yuanfei Zhu ^h ,
Siying Dong ^b ,
Hui Kong ^a ,
Honghua Wang ^c ,
Ji Jiang ^e ,
Mingyue Wan ⁱ ,
Mingyang Feng ⁱ ,
Qiang Deng ^h ,
Yumin Xu ^i,, ,
Qing You ^j,, ,
Ronggui Hu ^b,c,,

a. State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China;
b. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China;
c. Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China;
d. Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China;
e. Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai 200234, China;
f. Department of Pathogenic Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China;
g. School of Medicine, Guizhou University, Guiyang 550025, China;
h. Key Laboratory of Medical Molecular Virology (MOE & MOH), School of Basic Medical Sciences, Fudan University, Shanghai 200032, China;
i. Department of Hospital Infection Management, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
j. School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China

Corresponding author: Xiangpeng Sheng, shengxiangpeng@ucas.ac.cn Yumin Xu, xym121@163.com Qing You, youqing@sjtu.edu.cn Ronggui Hu, coryhu@sibcb.ac.cn
Received Date: 14 April 2023
Accepted Date: 24 January 2024

Abstract

Highlights
1. The expression level of TRIM21 in patients is negatively correlated with the replication and integration of HBV.
2. TRIM21 was found to trigger non-proteolytic ubiquitination of X protein of HBV.
3. This study proposes that the PRYSPRY and RING domains in TRIM21 dimer can form a docking conformation for HBx binding.
4. TRIM21-mediated HBx ubiquitination disrupts the DDB1 recruitment to HBx and stabilize Smc6.

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Proportional views
Electronic Supplementary Material

10.1016j.virs.2024.01.008-ESM.docx